Hand1 is a basic helix-loop-helix transcription factor involved in cell fate determination. One of its roles is in the differentiation of trophoblast stem cells to trophoblast giant cells (TGs), a process critical for the formation of the placenta. Martindill et al. show that Hand1 is localized in the nucleolus in a proliferating trophoblast-like cell line and is released from the nucleolus to spread throughout the nucleus at the onset and during differentiation into TGs. This process appears to involve phosphorylation of Hand1 by the polo-like kinase Plk4, the abundance of which increases at the onset of differentiation, which is localized to the nucleolus during the G2-to-mitosis transition. (Plk4 is also involved in exit from the mitotic cycle and the onset of endoreplication, which are involved in TG specification.) In addition, the regulatory subunit (B56δ) of protein phosphatase 2A was present in the nucleus, including the nucleolus in proliferating cells, and redistributes to the cytoplasm during TG differentiation. Overexpression of B56δ prevented nucleolar release of Hand1 and TG differentiation. The sequestration of Hand1 in the nucleolus appeared to involve a protein of the HIC family of transcriptional repressors, HICp40, because knockdown of this protein promoted release of Hand1 from the nucleolus and promoted TG differentiation, whereas overexpression prevented these events. Thus, it appears that dynamic subnuclear movement of Hand1, controlled by phosphorylation by Plk4, couples Hand1 to TG differentiation (see Tanenbaum and Medema for commentary).
D. M. J. Martindill, C. A. Risebro, N. Smart, M. Del Mar Franco-Viseras, C. O. Rosario, C. J. Swallow, J. W. Dennis, P. R. Riley, Nucleolar release of Hand1 acts as a molecular switch to determine cell fate. Nat. Cell Biol. 9, 1131-1141 (2007). [PubMed]
M. E. Tanenbaum, R. H. Medema, Cell fate in the hand of Plk4. Nat. Cell Biol. 9, 1127-1129 (2007). [PubMed]